PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Metagenomic studies in humans and animal models have established that there are alterations of the GI microbiota community during development of neoplastic and pre-neoplastic disease, and in tumor-bearing vs. healthy individuals. Understanding the impact of human host/microbiota interactions on the initiation, progression and treatment of cancer, and the molecular mechanisms that govern the outcomes of these interactions, will provide new therapeutic strategies and new targets for the treatment of many human tumors.

One promising approach emerging from recent research is alteration of microbiome function designed to enhance the efficacy of cancer therapies. Recent work demonstrated that individual variability in patient drug response to chemo (and other) therapies can be attributed to actions of the gastrointestinal (GI) microbiota, either through direct metabolic activity on the agent itself, or by effects on host barrier function and immunomodulation that affect drug efficacy. For example, microbial β-glucuronidase activity results in re-activation of toxic metabolites that affect the dose-limiting range of CPT-11, a prodrug form of the topoisomerase inhibitor Irinotecan that is widely used to treat a variety of solid tumors. Antibiotic co-therapy and specific inhibition of bacterial β-glucuronidase activity reduced chemotherapy-induced GI toxicity in several animal models. Other studies have shown that depletion of ROS-regulating Lactobacillus species by antibiotics, results in reduced tumoricidal activity of platinum based drugs. Similarly, the antitumor effects of radiotherapy and several cytotoxic chemotherapeutic drugs such as cyclophosomide (CTX), oxaliplatin, and CpG-ODN, are achieved in part by an immune-mediated bystander effect that requires the recruitment and activation of an intense inflammatory infiltrate to regress tumors.

In addition, the anti-tumor response to immune checkpoint inhibitors of CTLA-1 and PD-L1 were found to be mediated through interactions with of B. fragilis or Bifidobacterium respectively, in tumor xenograft models. When these bacteria were depleted, response to immunotherapy was significantly diminished. As we learn more about how the microbiome affects disease progression and response to treatments, the opportunity to exploit the microbiome for therapeutic benefit is an exciting new approach that should be explored.

Project Goals

The purpose of this SBIR contract solicitation is to develop innovative technologies and methods designed to modulate the GI microbiota in order to enhance the therapeutic efficacy of existing or novel cancer therapies, or ameliorate side effects of these therapies. The goal is to develop effective adjuvant strategies that specifically target critical microbial activities or populations that affect drug efficacy and/or tolerability. Ultimately, this activity will accelerate the development of novel strategies based on the rational targeting and manipulation of human GI microbiome functions for the treatment of human tumors.

To successfully meet this goal, applicants will need to demonstrate that their approach accomplishes the specific perturbation or modulation of microbial function that is desired, and that these approaches have demonstrable benefits in addressing a significant unmet medical need relevant to cancer (e.g. reduction of off-target toxicity). Phase I studies should focus on developing and refining the approach that will be used to modulate GI microbiota or functions performed by the microbiota (such as metabolic or immunomodulatory activity). Applicants should establish appropriate criteria to benchmark or evaluate the success of their approach, and these should be related to the expected level of perturbation or modulation that is required to have therapeutic benefits. Phase II studies should focus on demonstrating that the approaches developed in Phase I studies are effective in an appropriate in vivo model system. Lead candidates should be developed and tested for efficacy in appropriate animal models, and Phase II studies should also measure agent delivery (e.g., probiotics, engineered phage, lipids, nano-particles) and pharmacokinetic targeting (e.g., reduction/increase of specific microbial enzyme activity, signaling ligand, or host interaction) in addition to measured endpoints of tumor regression and/or ablation in vivo.

Applicants are required to identify and justify a cancer type and unmet medical need that can be addressed by their approach. They should also provide a scientifically justified rationale for exploring particular approach(es) for perturbing or modulating the microbiome, and justify the choice of model system to evaluate their approach(es).

It is anticipated that applicants will test perturbations of the GI microbiome such as, antibiotic treatments, bacteriophage therapies, probiotic supplements, dietary metabolites, drug metabolizing enzymes, modulators of bacterial metabolism, and immunomodulators. However, applicants are free to employ any approach.

The focus of this contract topic is not to search for new mechanisms or effects by which the microbiome affects cancer therapy or progression, but rather to explore microbiome directed intervention strategies that have a rational basis. The contract topic is not intended to develop screening approaches, though applicants may propose to refine or optimize lead compounds or other agents designed to modulate or perturb GI microbiota.

Phase I Activities and Deliverables

Define and characterize a host/microbe interaction that affects therapeutic efficacy, demonstrated through appropriate in vitro and in vivo experiments.

Develop targeted microbiota regulated/directed intervention strategies designed to improve, either alone or in combination, patient outcomes for new or current therapeutic agents. Approaches may involve, but are not limited to:

Test and refine therapeutic approaches in order to identify lead candidates or agent (e.g. bacteriophage, bacterial strain, enzyme, dietary metabolite, vaccine, etc.) to develop further in Phase II studies

The lead candidate or agent should be able to successfully accomplish the desired perturbation or modulation of the microbiome to a level that can reasonably be expected to be have an impact on the efficacy of the therapeutic interventions and demonstrate proof of concept for the efficacy of their approach. Offeror should demonstrate proof of concept in an appropriate in vivo model

Offeror should determine and justify the assays and endpoints that will be used to evaluate the success of their approach (e.g., biomarkers, enzymatic activity, presence or absence of specific microbial populations). If needed, offeror should develop alternative tools/methods to evaluate candidate effects on microbiome function.

Submit a statement to NCI that specifies the metrics and criteria used to evaluate the success of the approach being developed, and justification for these metrics and criteria from a commercial and scientific perspective.

Phase II Activities and Deliverables

Phase II activities should support commercialization of the proposed agent for clinical use. Expected activities and deliverables may include:

Demonstrate the efficacy of lead candidate(s) or agent(s) from Phase I studies in an appropriately characterized in vivo model

Evaluate toxicity and efficacy of therapeutic candidate(s) or agent(s)

Evaluate immune response to therapeutic approach where appropriate

Determine the toxicology and safety profile of the lead candidate(s) or agent(s) using appropriate animal models and assays relevant to the specific therapeutic approach being pursued

Optimize or scale up lead candidate(s) or agent(s) (e.g. bacteriophage, bacterial strain, enzyme, dietary metabolite, vaccine, etc.) from Phase I studies. Activities may include, but are not restricted to:

Medicinal chemistry to optimize small molecules for in vivo studies

Scale up production of lead therapeutic candidate(s) or agent(s)

Optimize delivery method for therapeutic candidate(s) or agent(s)

Develop a plan for obtaining regulatory approval to conduct human studies. Offerors should provide plans and a detailed time table for obtaining this regulatory approval